Treatment of inflammation and inflammation-related disorders with a combination of a cyclooxygenase-2 inhibitors and a leukotriene B4 receptor antagonist

ABSTRACT

Combinations of a cyclooxygenase-2 inhibitor and a leukotriene B 4  receptor antagonist are described for treatment of inflammation and inflammation-related disorders.

RELATED CASE

This is a continuation-in-part of U.S. application Ser. No.08/489,415,with a filing date of Jun. 12, 1995.

FIELD OF THE INVENTION

This invention is in the field of antiinflammatory pharmaceutical agentsand specifically relates to co-administration of an inhibitor ofcyclooxygenase-2 and a leukotriene B₄ receptor antagonist for treatinginflammation and inflammation-related disorders, such as arthritis.

BACKGROUND OF THE INVENTION

Prostaglandins play a major role in the inflammation process, and theinhibition of prostaglandin production, especially production of PGG₂,PGH₂ and PGE₂, has been a common target of antiinflammatory drugdiscovery. However, common non-steroidal antiinflammatory drugs (NSAIDs)that are active in reducing the prostaglandin-induced pain and swellingassociated with the inflammation process are also active in affectingother prostaglandin-regulated processes not associated with theinflammation process. Thus, use of high doses of most common NSAIDs canproduce severe side effects, including life threatening ulcers, thatlimit their therapeutic potential. An alternative to NSAIDs is the useof corticosteroids, which have even more drastic side effects,especially when long term therapy is involved.

Previous NSAIDs have been found to prevent the production ofprostaglandins by inhibiting enzymes in the human arachidonicacid/prostaglandin pathway including the enzyme cyclooxygenase (COX).The recent discovery of an inducible enzyme associated with inflammation(named “cyclooxygenase-2 (COX-2)” or “prostaglandin G/H synthase II”)provides a viable target of inhibition which more effectively reducesinflammation and produces fewer and less drastic side effects.

In another portion of the arachidonic acid pathway, physiologicallyactive leukotrienes, such as leukotriene B₄ (LTB₄), leukotriene C₄(LTC₄) and leukotriene D₄ (LTD₄) and other metabolites, are produced bythe 5-lipoxygenase-mediated (5-LO) oxidation of arachidonic acid. Theseleukotrienes have been implicated in various inflammation-relateddisorders and allergic diseases, and thus compounds which inhibitleukotriene A₄ conversion to leukotriene B₄, such as compounds whichinhibit leukotriene A₄ hydrolase are useful in the treatment of diseasestates in which leukotrienes play an important role.

It is believed that selective inhibitors of cyclooxygenase-2 and ofleukotriene A₄ hydrolase, which affect the two enzymes at lowconcentrations, will decrease the incidence and severity morecompletely. These compositions also will beneficially affect the damagecaused by the various inflammatory diseases and inflammation-relateddisorders mediated by cyclooxygenase-2 and leukotriene A₄ hydrolase.These compositions also will not have the level of gastrointestinal sideeffects commonly associated with traditional NSAIDs.

Compounds which selectively inhibit cyclooxygenase-2 have been describedin U.S. Pat. Nos. 5,380,738, 5,344,991, 5,393,790, 5,466,823, 5,434,178,5,474,995, 5,510,368 and WO documents WO96/06840, WO96/03388,WO96/03387, WO95/15316, WO94/15932, WO94/27980, WO95/00501, WO94/13635,WO94/20480, and WO94/26731.

Compounds which affect leukotriene B₄ have been described. U.S. Pat. No.5,384,318 describes substituted sulfonamides for the treatment ofasthma. U.S. Pat. No. 5,246,965 describes aryl ethers as leukotriene B₄receptor antagonists.

Combined therapies of NSAIDs and other reagents are known in the art.Brooks and Karl describe the treatment of hay fever with combinedantihistamines and a cyclooxygenase-inhibiting drug (flurbiprofen) (J.Allergy Clin. Immunol., 81, 110 (1988)). J. Basmajian (Spine, 14, 438(1989)) describes the combination of the analgesic diflunisal and anantispasm agent in the treatment of back pain. V. Fossaluzza and S.DeVita describe the combined therapy of ibuprofen and an antispasm agentto reduce morning stiffness associated with primary fibromyagliasyndrome (Int. J. Clin. Pharm. Res., XII, 99 (1992)). R. Greenwald etal. (J. Rheumatol., 19, 927 (1992)) report the combination oftetracycline and the NSAID flurbiprofen ameliorates the tissue damageassociated with rheumatoid arthritis.

Combination analgesics have been reported (W. Beaver, Am. J. Med., 77,38 (1984)) although such combinations do not substantially reduceadverse effects.

The combination of NSAIDs and steroids have been described. Acombination of indomethacin, steroid and lipopolysaccharide has beenreported for the treatment of spinal injury (L. Guth et al., Proc. Natl.Acad. Sci. USA, 91, 12308 (1994)). G. Hughes et al. describecombinations of corticosteroids with NSAIDs for the treatment of sunburn(Dermatology, 184, 54 (1992)). C. Stewart et al. (Clin. Pharmacol.Ther., 47, 540 (1990)) describe the combination of naproxen andmethotrexate as safe, although concurrent administrations ofmethotrexate with other NSAIDs have been reported to be toxic andsometimes fatal. A combination of a dual 5-lipoxygenase/cyclooxygenaseinhibitor with a glucocorticoid is described for the treatment of skindisorders (K. Tramposch, Inflammation, 17, 531 (1993)). Combinations ofNSAIDs and steroids should be used in the treatment of scleritis only ifpatients are not responsive to any other treatment (S. Lightman and P.Watson, Am. J. Ophthalmol., 108, 95 (1989)).

Combinations of cyclooxygenase inhibitors, lipoxygenase inhibitors,collagenase inhibitors and cytotoxic agents have been used in thetreatment of non-small-cell lung cancers (B. Teicher et al., Cancer.Chemother. Pharmacol., 33, 515 (1994)).

Combinations of naproxen with other NSAIDs have been described in thetreatment of arthritis. R. Willikens and E. Segre (Arthritis Rheum., 19,677 (1976)) describe the combination of aspirin and naproxen as beingmore effective than aspirin alone for the treatment of rheumatoidarthritis. Naproxen and acetaminophen together were described fortreating the pain associated with arthritis (P. Seideman et al., ActaOrthop. Scand., 64, 285 (1993)). However, combinations of naproxen withindomethacin or ibuprofen offer no advantage in the treatment ofarthritis [M. Seifert and C. Engler (Curr. Med. Res. Opin., 7, 38(1980))]. European patent document EP485,111, published May 13, 1992,describes the synergistic combination of lipoxygenase inhibitors andNSAID's for the treatment of inflammatory disease.

There have been no reported combinations of a cyclooxygenase-2 selectiveinhibitor and a leukotriene B₄ receptor antagonist.

DESCRIPTION OF THE INVENTION

The invention involves a method of treating a subject havinginflammation or an inflammation-related disorder with a combinationcomprising a therapeutically-effective amount of a cyclooxygenase-2inhibitor and a leukotriene B4 receptor antagonist.

In addition, the invention describes a combination comprising atherapeutically-effective amount of a leukotriene B₄ receptor antagonistand a cyclooxygcnase-2 inhibitor selected from Taisho NS-398(Methanesulfonamide, N-[2-(cyclohexyloxy)-4-nitrophenyl]), meloxicam(2H-1,2-Benzothiazine-3-carboxamide,4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-, 1,1-dioxide), [floculide]flosulide (Methaflesulfonamide,N-[6-(2,4-difluorophenoxy)-2,3-dihydro-1-oxo-1H-inden-5-yl]), MerckMK-966 (2(5H)-Furanone, 4-[4-(methylsulfonyl)phenyl]-3-phenyl), MerckL-752,860 and compounds of Formula I.

wherein A is a substituent selected from partially unsaturated orunsaturated heterocyclyl and partially unsaturated or unsaturatedcarbocyclic rings;

wherein R¹ is at least one substituent selected from heterocyclyl,cycloalkyl, cycloalkenyl and aryl, wherein R¹ is optionally substitutedat a substitutable position with one or more radicals selected fromalkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl,hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro,alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;

wherein R² is methyl or amino; and

wherein R³ is a radical selected from hydrido, halo, alkyl, alkenyl,alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy,alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl,cycloalkenyl, aralkyl, heterocyclylalkyl, acyl, alkylthioalkyl,hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl,alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl,aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl,aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl,N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl,alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino,N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl,N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl,N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio,alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl,N-arylaminosulfonyl, arylsulfonyl, N-alkyl-N-arylaminosulfonyl;

or a pharmaceutically-acceptable salt thereof.

Combinations of the invention would be useful for, but not limited to,the treatment of inflammation in a subject, and for treatment of otherinflammation-associated disorders, such as, as an analgesic in thetreatment of pain and headaches, or as an antipyretic for the treatmentof fever. For example, combinations of the invention would be useful totreat arthritis, including but not limited to rheumatoid arthritis,spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupuserythematosus and juvenile arthritis. Such combinations of the inventionwould be useful in the treatment of asthma, bronchitis, menstrualcramps, tendinitis, bursitis, and skin related conditions such aspsoriasis, eczema, burns and dermatitis. Combinations of the inventionalso would be useful to treat gastrointestinal conditions such asinflammatory bowel disease, Crohn's disease, gastritis, irritable bowelsyndrome and ulcerative colitis and for the prevention or treatment ofcancer, such as colorectal cancer. Combinations of the invention wouldbe useful in treating inflammation in such diseases as vasculardiseases, migraine headaches, periarteritis nodosa, thyroiditis,aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type Idiabetes, myasthenia gravis, multiple sclerosis, sarcoidosis, nephroticsyndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensitivity,swelling occurring after injury, myocardial ischemia, and the like. Thecompounds would also be useful in the treatment of ophthalmic diseases,such as retinitis, retinopathies, conjunctivitis, uveitis, ocularphotophobia, and of acute injury to the eye tissue. The compounds wouldalso be useful in the treatment of pulmonary inflammation, such as thatassociated with viral infections and cystic fibrosis. The compoundswould also be useful for the treatment of certain central nervous systemdisorders such as cortical dementias including Alzheimer's disease. Thecombinations of the invention are useful as anti-inflammatory agents,such as for the treatment of arthritis, with the additional benefit ofhaving significantly less harmful side effects. As inhibitors of5-lipoxygenase, these compositions would also be useful in the treatmentof allergic rhinitis, respiratory distress syndrome, endotoxin shocksyndrome, atherosclerosis and central nervous system damage resultingfrom stroke, ischemia and trauma.

Besides being useful for human treatment, these compounds are alsouseful for treatment of mammals, including horses, dogs, cats, rats,mice, sheep, pigs, etc.

The term “cyclooxygenase-2 inhibitor” embraces compounds whichselectively inhibit cyclooxygenase-2 over cyclooxygenase-1. Preferably,the compounds have a cyclooxygenase-2 IC₅₀ of less than about 0.5 μM,and also have a selectivity ratio of cyclooxygenase-2 inhibition overcyclooxygenase-1 inhibition of at least 50, and more preferably of atleast 100. Even more preferably, the compounds have a cyclooxygenase-1IC₅₀ of greater than about 1 μM, and more preferably of greater than 20μM. Such preferred selectivity may indicate an ability to reduce theincidence of common NSAID-induced side effects.

The term “leukotriene B₄ receptor antagonist” embraces compounds whichselectively antagonize a leukotriene B₄ receptor with an IC₅₀ of lessthan about 10 μM. More preferably, the leukotriene B₄ receptorantagonists have an IC₅₀ of less than about 1 μM.

The phrases “combination therapy”, “co-administration” or “co-therapy”,in defining use of a cyclooxygenase-2 inhibitor agent and a leukotrieneB₄ receptor antagonist agent, are intended to embrace administration ofeach agent in a sequential manner in a regimen that will providebeneficial effects of the drug combination, and is intended as well toembrace co-administration of these agents in a substantiallysimultaneous manner, such as in a single capsule having a fixed ratio ofthese active agents or in multiple, separate capsules for each agent.

The phrase “therapeutically-effective” is intended to qualify the amountof each agent for use in the combination therapy which will achieve thegoal of improvement in inflammation severity and the frequency ofincidence over treatment of each agent by itself, while avoiding adverseside effects typically associated with alternative therapies.

Preferred leukotriene B₄ receptor antagonists incluce Bayer Bay-x-1005((R)-a-Cyclopentyl-4-(2-quinolinylmethoxy) benzene acetic acid),Ciba-Geigy CGS-25019C (Benzamide,4-[[5-[4-(aminoiminomethyl)phenoxy]pentyl]oxy]-3-methoxy-N,N-bis(1-methylethyl)-,(2Z)-2-butenedioate), ebselen (1,2-Benzisoselenazol-3 (2H)-one,2-phenyl), Leo Denmark ETH-615 (Benzoic acid,4-[[[(3-fluorophenyl)methyl][4-(2-quinolinylmethoxy)phenyl]amino]methyl]), Lilly LY-29311(Benzoic acid,2-[3-[3-[(5-ethyl-4′-fluoro- 2-hydroxy [1,1′-biphenyl]-4-yl)oxy]propoxy]-2-propylphenoxyl]), Ono ONO-4057 (Benzenepropanoic acid,2-(4-carboxybutoxy)-6-[[(5E)-6-(4-methoxyphenyl)-5-hexenyl]oxy]), TerumoTMK-688 (Carbonic acid,4-[5-[[2-[4-(diphenylmethoxy)-1-piperidinyl]ethyl]amino]-5-oxo-1,3-pentadienyl]-2-methoxyphenylethyl ester), Boehringer Ingleheim BI-RM-270 (2-Benzoxazolamine,N-[(1S)-2-cyclohexyl-1-(2-pyridinyl)ethyl]-5-methyl), Lilly LY 213024(Benzenepropanoic acid, 5-(3-carboxybenzoyl)-2-(decyloxy)), Lilly LY264086 (9H-Xanthene-4-propanoic acid, 7-carboxy-3-(decyloxy)-9-oxo),Lilly LY 292728, Ono ONO LB457 (Benzenepropanoic acid,2-(4-carboxybutoxy)-6-[[(5E)-6-(4-methoxyphenyl)-5-hexenyl]oxy]), Pfizer105696, Perdue Frederick PF 10042 (Pyrrolidine,1-[5-hydroxy-5-[8-(1-hydroxy-2-phenylethyl)-2-dibenzofuranyl]-1-oxopentyl]),Rhone-Poulenc Rorer RP 66153 (2-Thiopheneheptanoic acid,alpha.,.alpha,-dimethyl-3-(3-phenylpropyl)), SmithKline BeechamSB-201146 (2-Propenoic acid,3-[6-[[(3-aminophenyl)sulfinyl]methyl]-3-[[8-(4-methoxyphenyl)octyl]oxy]-2-pyridinyl]-,(2E)), SmithKline Beecham SB201993 (Benzoic acid,3-[[[[6-[(1E)-2-carboxyethenyl]-5-[[8-(4-methoxyphenyl)octyl]oxy]-2-pyridinyl]methyl]thio]methyl]),Searle SC-53228 (2H-1Benzopyran-2-propanoic acid,7-[3-[2-(cyclopropylmethyl)-3-methoxy-4-[(methylamino)carbonyl]phenoxy]propoxy]-3,4-dihydro-8-propyl-,(2S)), Sumitamo SM 15178 (.beta.-Alanine,N-[[6-[(4-acetyl-2-ethyl-5-hydroxyphenoxy)methyl]-2-pyridinyl]carbonyl]N-ethyl),American Home Products WAY 121006 ([1,1′-Biphenyl]-4-acetic acid,2-fluoro-4′-(2-quinolinylmethoxy)), Bayer Bay-o-8276, calcitriol(9,10-Secochlolesta-5,7,10(19)-triene-1,3,25-triol,(1.alpha.,3.beta.,5Z,7E)), Warner-Lambert CI-987(2,4-Thiazolidinedione,5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]),Merck and Co. L-651392 (3H-Phenothiazin-3-one, 4-bromo-2,7-dimethloxy),Lilly LY 210073, Lilly LY 223982 (Benzenepropanoic acid,5-(3-carboxybenzoyl)-2-[[(5E)-6-(4-methoxyphenyl)-5-hexenyl]oxy]), LillyLY-233569 (2-Propenamide, N-hydroxy-N-methyl-3-[2-(methylthio)phenyl]),Lilly LY-255283 (Ethanone,1-[5-ethyl-2-hydroxy-4-[[6-methyl-6-(1H-tetrazol-5-yl)heptyl]oxy]phenyl]),Merck and Co.

MK-591 (1H-Indole-2-propanoic acid,1-[(4-chlorophlenyl)methyl]-3-[(1,1-dimethylethyl)thio]-a,a-dimethyl-5-(2-quinolinylmethoxy)-, sodiumn salt), Merck and CO. MK-886(1H-indole-2-propanoic acid,1-[(4-chlorophenyl)methyl]-3-[(1,1-dimethlylethyl)thio]-a,a-dimethyl-5-(1-methylethyl)), Ono ONO-LB-448, Purdue Frederick PF-5901(Benzenemethanol, a-pentyl-3-(2-quinolinylmethoxy)), Rhone-Poulenc RorerRG 14893 (2-Naphthalenecarboxylic acid,4-[2-[methyl(2-phenylethyl)amino]-2-oxoethyl]-8-(phenylmethoxy)),Rhone-Poulenc Rorer RP 66364, Rhone-Poulenc Rorer RP 69698 (Pyridine,2-[[5-methyl-5-(1H-tetrazol-5-yl)hexyl]oxy]-4,6-diphenyl), SearleSC-41930 (2H-1-Benzopyran-2-carboxylic acid,7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-3,4-dihydro-8-propyl),Searle SC-50505, Searle SC-51146, SmithKline Beecham SK&F-104493(5H-Pyrrolo[1,2-a]imidazole,6,7-dihydro-2-(4-methoxyphenyl)-3-(4-pyridinyl)) and Teinjin TEI-1338(Benzoic acid,2-[[4-[2-[2-(2-naphthalenyl)ethenyl]cyclopropyl]-1-oxobutyl]amino]-,methyl ester, [1R-[1.alpha.,2.beta.(E)]]).

More preferred leukotrieiie B₄ receptor antagonists include BayerBay-x-1005 ((R)-a-Cyclopentyl-4-(2-quinolinylmethoxy)benzeneaceticacid), Ciba-Geigy CGS-25019C (Benzamide,4-[[5-[4-(aminoiminomethyl)phenoxy]pentyl]oxy]-3-methoxy-N,N-bis(1-methylethyl)-, (2Z)-2-butenedioate), ebselen (1,2-Benzisoselenazol-3(2H)-one, 2-phenyl), Leo Denmark ETH-615 (Benzoic acid,4-[[[(3-fluorophenyl)methyl][4-(2-quinolinylmethoxy)phenyl]amino]methyl]),Lilly LY-293111 (Benzoic acid, 2-[3-[3-[(5-ethyl-4′fluoro-2-hydroxy[1,1′-biphenyl]-4-yl)oxy]propoxy]-2-propylphenoxy]), Ono ONO-4057(Benzenepropanoic acid,2-(4-carboxybutoxy)-6-[[(5E)-6-(4-methoxyphenyl)-5-hexenyl]oxy]), TerumoTMK-688 (Carbonic acid,4-[5-[[2-[4-(diphenylmethoxy)-1-piperidinyl]ethyl]amino]-5-oxo-1,3-pentadienyl]-2-methoxyphenylethyl ester), Boehringer Ingleheim BI-RM-270 (2-Benzoxazolamine,N-[(1S)-2-cyclohexyl-1-(2-pyridinyl)ethyl]-5-methyl), Lilly LY 213024(Benzenepropanoic acid, 5-(3-carboxybenzoyl)-2-(decyloxy)), Lilly LY264086 (9H-Xanthene-4-propanoic acid, 7-carboxy-3-(decyloxy)-9-oxo),Lilly LY 292728, Ono ONO LB457 (Benzenepropanoic acid,2-(4-carboxybutoxy)-6-[[(5E)-6-(4-methoxyphenyl)-5-hexenyl]oxy]), Pfizer105696, Perdue Frederick PF 10042 (Pyrrolidine,1-[5-hydroxy-5-[8-(1-hydroxy-2-phenylethyl)-2-dibenzofuranyl]-1-oxopentyl]),Rhone-Poulenc Rorer RP 66153 (2-Thiopheneheptanoic acid,.alpha.,.alpha.-dimethyl-3-(3-phenylpropyl)), SmithKline BeechamSB-201146 (2-Propenoic acid,3-[6-[[(3-aminophenyl)sulfinyl]methyl]-3-[[8-(4-methoxyphenyl)octyl]oxy]-2-pyridinyl]-,(2E)), SmithKline Beecham SB-201993 (Benzoic acid,3-[[[[6-[(1E)-2-carboxyethenyl]-5-[[8-(4-methoxyphenyl)octyl]oxy]-2-pyridinyl]methyl]thio]methyl]),Searle SC-53228 (2H-1-Benzopyran-2-propanoic acid,7-[3-[2-(cyclopropylmethyl)-3-methoxy-4-[(methylamino)carbonyl]phenoxy]propoxy]-3,4-dihydro-8-propyl-(2S)), Sumitamo SM 15178(.beta.-Alanine,N-[[6-[(4-acetyl-2-ethyl-5-hydroxyphenoxy)methyl]-2-pyridinyl]carbonyl]-N-ethyl),and American Home Products WAY 121006 ([1,1′-Biphenyl]-4-acetic acid,2-fluoro-4′-(2-quinolinylmethoxy)).

Even more preferred leukotriene B₄ receptor antagonists include BayerBay-x-1005 ((R)-a-Cyclopentyl-4-(2-quinolinylmethoxy)benzeneaceticacid), Ciba-Geigy CGS-25019C (Benzamide,4-[[5-[4-(aminoiminomethyl)phenoxy]pentyl]oxy]-3-methoxy-N,N-bis(1-methylethyl)-, (2Z)-2-butenedioatc), ebselen (1,2-Benzisoselenazol-3(2H)-one, 2-phenyl), Leo Denmark ETH-615 (Benzoic acid,4-[[[(3-fluorophenyl)methyl][4-(2-quinolinylmethoxy)phenyl]amino]methyl]),Lilly LY-293111 (Benzoic acid,2-[3-[3-[(5-ethyl-4′-fluoro-2-hydroxy[1,1′-biphenyl]-4-yl)oxy]propoxy]-2-propylphenoxy]);Ono ONO-4057 (Benzenepropanoic acid,2-(4-carhoxybutoxy)-6-[[(5E)-6-(4-methoxyphenyl)-5-hexenyl]oxy]), andTerumo TMK-688 (Carbonic acid,4-[5-[[2-[4-(diphenylmethoxy)-1-piperidinyl]ethyl]amino]-5-oxo-1,3-pentadienyl]-2-methoxyphenylethyl ester).

A preferred class of compounds which inhibit cyclooxygenase-2 consistsof compounds of Formula I wherein A is selected from 5- or 6-memberpartially unsaturated heterocyclyl, 5- or 6-member unsaturatedheterocyclyl, 9- or 10-member unsaturated condensed heterocyclyl, lowercycloalkenyl and phenyl; wherein R¹ is selected from 5- and 6-memberedheterocyclyl, lower cycloalkyl, lower cycloalkenyl and aryl selectedfrom phenyl, biphenyl and naphthyl, wherein R¹ is optionally substitutedat a substitutable position with one or more radicals selected fromlower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl,hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino,phenylamino, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxyand lower alkylthio; wherein R² is methyl or amino; and wherein R³ is aradical selected from hydrido, oxo, cyano, carboxyl, loweralkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, halo, lower alkyl,lower alkyloxy, lower cycloalkyl, phenyl, lower haloalkyl, 5- or6-membered heterocyclyl, lower hydroxylalkyl, lower aralkyl, acyl,phenylcarbonyl, lower alkoxyalkyl, 5- or 6-membered heteroaryloxy,aminocarbonyl, lower alkylaminocarbonyl, lower alkylamino, loweraminoalkyl, lower alkylaminoalkyl, phenyloxy, and lower aralkoxy; or apharmaceutically-acceptable salt thereof.

A more preferred class of compounds which inhibit cyclooxygenase-2consists of compounds of Formula I wherein A is selected from oxazolyl,isoxazolyl, thienyl, dihydrofuryl, furyl, pyrrolyl, pyrazolyl,thiazolyl, imidazolyl, isothiazolyl, benzofuryl, cyclopentenyl,cyclopentadienyl, phenyl, and pyridyl; wherein R¹ is selected frompyridyl optionally substituted at a substitutable position with one ormore methyl radicals, and phenyl optionally substituted at asubstitutable position with one or more radicals selected from methyl,ethyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, cyano,fluoromethyl, difluoromethyl, trifluoromethyl, carboxyl,methoxycarbonyl, ethoxycarbonyl, hydroxymethyl, trifluoromethoxy,hydroxyl, amino, N-methylamino, N,N-dimethylamino, N-ethylamino,N,N-dipropylamino, N-butylamino, N-methyl-N-ethylamino, phenylamino,methoxymethyl, methylsulfinyl, fluoro, chloro, bromo, methoxy, ethoxy,propoxy, n-butoxy, pentoxy, and methylthio; wherein R² is methyl oramino; and wherein R³ is a radical selected from hydrido, oxo, cyano,carboxyl, methoxycarbonyl, ethoxycarbonyl, carboxypropyl, carboxymethyl,carboxyethyl, cyanomethyl, fluoro, chloro, bromo, methyl, ethyl,isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, difluoromethyl,trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluoroethyl,difluoropropyl, methoxy, ethoxy, propoxy, n-butoxy, pentoxy, cyclohexyl,phenyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl, pyrazinyl,hydroxylmethyl, hydroxylpropyl, benzyl, formyl, phenylcarbonyl,methoxymethyl, furylmethyloxy, aminocarbonyl, N-methylaminocarbonyl,N,N-dimethylaminocarbonyl, N,N-dimethylamino, N-ethylamino,N,N-dipropylamino, N-butylamino, N-methyl-N-ethylamino, aminomethyl,N,N-dimethylaminomethyl, N-methyl-N-ethylaminomethyl, benzyloxy, andphenyloxy; or a pharmaceutically-acceptable salt thereof.

A family of specific compounds of particular interest within Formula Iconsists of compounds and pharmaceutically-acceptable salts thereof asfollows:

5-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole;

4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-1-phenyl-3-(trifluoromethyl)pyrazole;

4-(5-(4-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazol-1-yl)benzenesulfonamide;

4-(3,5-bis(4-methylphenyl)-1H-pyrazol-1-yl)benzenesulfonamide;

4-(5-(4-chlorophenyl)-3-phenyl-1H-pyrazol-1-yl)benzenesulfonamide;

4-(3,5-bis(4-methoxyphenyl)-1H-pyrazol-1-yl)benzenesulfonamide;

4-(5-(4-chlorophenyl)-3-(4-methylphenyl)-1H-pyrazol-1-yl)benzenesulfonamide;

4-(5-(4-chlorophenyl)-3-(4-nitrophenyl)-1H-pyrazol-1-yl)benzenesulfonamide;

4-(5-(4-chlorophenyl)-3-(5-chloro-2-thienyl)-1H-pyrazol-1-yl)benzenesulfonamide;

4-(4-chloro-3,5-diphenyl-1H-pyrazol-1-yl)benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1yl]benzenesulfonamide;

4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(difluoromethyl)-5-(4-methylphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(difluoromethyl)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(difluoromethyl)-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[4-chloro-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-chlorophenyl)-3-(hydroxymethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;

4-[6-(4-fluorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide;

6-(4-fluorophenyl)-7-[4-(methylsulfonyl)phenyl]spiro[3.4]oct-6-ene;

5-(3-chloro-4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;

4-[6-(3-chloro-4-methoxyphenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide;

5-(3,5-dichloro-4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;

5-(3-chloro-4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;

4-[6-(3,4-dichlorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide;

2-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)thiazole;

2-(2-chlorophenyl)-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)thiazole;

5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-methylthiazole;

4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-trifluoromethylthiazole;

4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(2-thienyl)thiazole;

4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-benzylaminothiazole;

4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(1-propylamino)thiazole;

2-[(3,5-dichlorophenoxy)methyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]thiazole;

5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethylthiazole;

1-methylsulfonyl-4-[1,1-dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien-3-yl]benzene;

4-[4-(4-fluorophenyl)-1,1-dimethylcyclopenta-2,4-dien-3-yl]benzenesulfonamide;

5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hepta-4,6-diene;

4-[6-(4-fluorophenyl)spiro[2.4]hepta-4,6-dien-5-yl]benzenesulfonamide;

6-(4-fluorophenyl)-2-methoxy-5-[4-(methylsulfonyl)phenyl]-pyridine-3-carbonitrile;

2-bromo-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-pyridine-3-carbonitrile;

6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-phenyl-pyridine-3-carbonitrile;

4-[2-(4-methylpyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;

4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;

4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;

3-[l-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;

2-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;

2-methyl-4-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;

2-methyl-6-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;

4-[2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;

2-(3,4-difluorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole;

4-[2-(4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesuifonamide;

2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-methyl-1H-imidazole;

2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-phenyl-1H-imidazole;

2-(4-chlorophenyl)-4-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole;

2-(3-fluoro-4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1H-imidazole;

1-[4-(methylsulfonyl)phenyl]-2-phenyl-4-trifluoromethyl-1H-imidazole;

2-(4-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole;

4-[2-(3-chloro-4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;

2-ethoxy-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine;

5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(2-propynyloxy)-6-(trifluoromethyl)pyridine;

2-bromo-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine;

4-[2-(3-chloro-4-methoxyphenyl)-4,5-difluorophenyl]benzenesulfonamide;

1-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;

5-difluoromethyl-4-(4-methylsulfonylphenyl)-3-phenylisoxazole;

4-[3-ethyl-5-phenylisoxazol-4-yl]benzenesulfonamide;

4-[5-difluoromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide;

4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide;

4-[5-methyl-3-phenyl-isoxazol-4-yl]benzenesulfonamide;

1-[2-(4-fluorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;

1-[2-(4-fluoro-2-methylphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;

1-[2-(4-chlorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;

1-[2-(2,4-dichlorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;

1-[2-(4-trifluoromethylphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;

1-[2-(4-methylthiophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;

1-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl]-4-(methylsulfonyl)benzene;

4-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl]benzenesulfonamide;

1-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl]-4-(methylsulfonyl)benzene;

4-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl]benzenesulfonamide;

2-(3-fluoro-5-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole;

4-[2-(3-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;

2-(3-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole;

4-[2-(3-methylphenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulfonamide;

1-[4-(methylsulfonyl)phenyl]-2-(3-chlorophenyl)-4-trifiuoromethyl-1H-imidazole;

4-[2-(3-chlorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulfonamide;

4-[2-phenyl-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulfonamide;

4-[2-(4-methoxy-3-chlorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulfonamide;

1-allyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole;

4-[1-ethyl-4-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzenesulfonamide;

N-phenyl-[4-(4-luorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetamide;

ethyl[4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetate;

4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-phenylethyl)-1H-pyrazole;

4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-phenylethyl)-5-(trifluoromethyl)pyrazole;

1-ethyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole;

5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethyl-1H-imidazole;

4-[4-(methylsulfonyl)phenyl]-5-(2-thiophenyl)-2-(trifluoromethyl)-1H-imidazole;

5-(4-fluorophenyl)-2-methoxy-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine;

4-[2-(4-fluorophenyl)cyclopenten-1-yl]benzenesulfonamide;

4-[2-(4-chlorophenyl)cyclopenten-1-yl]benzenesulfonamide;

1-[2-(4-methoxyphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;

1-[2-(2,3-difluorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;

4-[2-(3-fluoro-4-methoxyphenyl)cyclopenten-1-yl]benzenesulfonamide;

1-[2-(3-chloro-4-methoxyphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;

4-[2-(3-chloro-4-fluorophenyl)cyclopenten-1-yl]benzenesulfonamide;

4-[2-(2-methylpyridin-5-yl)cyclopenten-1-yl]benzenesulfonamide;

ethyl 2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazol-2-yl]-2-benzyl-acetate;

2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazol-2-yl]aceticacid;

2-(tert-butyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazole;

4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-phenyloxazole;

4-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]oxazole; and

4-[5-(3-fluoro-4-methoxyphenyl)-2-trifluoromethyl-4-oxazolyl]benzenesulfonamide.

A family of specific compounds of more particular interest withinFormula I consists of compounds and pharmaceutically-acceptable saltsthereof as follows:

4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;

2-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;

4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;

4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide;

4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide;

[2-trifluoromethyl-5-(3,4-difluorophenyl)-4-oxazolyl]benzenesulfonamide;

4-[2-methyl-4-phenyl-5-oxazolyl]benzenesulfonamide; and

4-[5-(3-fluoro-4-methoxyphenyl-2-trifluoromethyl)-4-oxazolyl]benzenesulfonamide.

The term “hydrido” denotes a single hydrogen atom (H). This hydridoradical may be attached, for example, to an oxygen atom to form ahydroxyl radical or two hydrido radicals may be attached to a carbonatom to form a methylene (—CH₂—) radical. Where used, either alone orwithin other terms such as “haloalkyl”, “alkylsulfonyl”, “alkoxyalkyl”and “hydroxyalkyl”, the term “alkyl” embraces linear or branchedradicals having one to about twenty carbon atoms or, preferably, one toabout twelve carbon atoms. More preferred alkyl radicals are “loweralkyl” radicals having one to about ten carbon atoms. Most preferred arelower alkyl radicals having one to about six carbon atoms. Examples ofsuch radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like.The term “alkenyl” embraces linear or branched radicals having at leastone carbon-carbon double bond of two to about twenty carbon atoms or,preferably, two to about twelve carbon atoms. More preferred alkylradicals are “lower alkenyl” radicals having two to about six carbonatoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl,propenyl, butenyl and 4-methylbutenyl. The term “alkynyl” denotes linearor branched radicals having two to about twenty carbon atoms or,preferably, two to about twelve carbon atoms. More preferred alkynylradicals are “lower alkynyl” radicals having two to about ten carbonatoms. Most preferred are lower alkynyl radicals having two to about sixcarbon atoms. Examples of such radicals include propargyl, butynyl, andthe like. The terms “alkenyl”, “lower alkenyl”, embrace radicals having“cis” and “trans” orientations, or alternatively, “E” and “Z”orientations. The term “cycloalkyl” embraces saturated carbocyclicradicals having three to twelve carbon atoms. More preferred cycloalkylradicals are “lower cycloalkyl”, radicals having three to about eightcarbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl. The term “cycloalkenyl” embraces partiallyunsaturated carbocyclic radicals having three to twelve carbon atoms.More preferred cycloalkenyl radicals are “lower cycloalkenyl” radicalshaving four to about eight carbon atoms. Examples of such radicalsinclude cyclobutenyl, cyclopentenyl, cyclopentadienyl and cyclohexenyl.The term “halo” means halogens such as fluorine, chlorine, bromine oriodine. The term “haloalkyll” embraces radicals wherein any one or moreof the alkyl carbon atoms is substituted with halo as defined above.Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkylradicals. A monohaloalkyl radical, for one example, may have either aniodo, bromo, chloro or fluoro atom within the radical. Dihalo andpolyhaloalkyl radicals may have two or more of the same halo atoms or acombination of different halo radicals. “Lower haloalkyl” embracesradicals having 1-6 carbon atoms. Examples of haloalkyl radicals includefluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, trichloromethyl, pentafluoroethyl,heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. Theterm “hydroxyalkyl” embraces linear or branched alkyl radicals havingone to about ten carbon atoms any one of which may be substituted withone or more hydroxyl radicals. More preferred hydroxyalkyl radicals are“lower hydroxyalkyl” radicals having one to siix carbon atoms and one ormore hydroxyl radicals. Examples of such radicals include hydroxymethyl,hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. The terms“alkoxy” and “alkyloxy” embrace linear or branched oxy-containingradicals each having alkyl portions of one to about ten carbon atoms.More preferred alkoxy radicals are “lower alkoxy” radicals having one tosix carbon atoms. Examples of such radicals include methoxy, ethoxy,propoxy, butoxy and tert-butoxy. The term “alkoxyalkyl” embraces alkylradicals having one or more alkoxy radicals attached to the alkylradical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals.The “alkoxy” radicals may be further substituted with one or more haloatoms, such as fluoro, chloro or bromo, to provide haloalkoxy radicals.More preferred haloalkoxy radicals are “lower haloalkoxy” radicalshaving one to six carbon atoms and one or more halo radicals. Examplesof such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy,trifluoroethoxy, fluoroethoxy and fluoropropoxy. The term “aryl”, aloneor in combination, means a carbocyclic aromatic system containing one,two or three rings wherein such rings may be attached together in apendent manner or may be fused. The term “aryl” embraces aromaticradicals such as phenyl, naphthyl, tetrahydronaphthyl, indane andbiphenyl. Aryl moieties may also be substituted at a substitutableposition with one or more substituents selected independently fromalkyl, alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl,aminocarbonylalkyl, alkoxy, aralkoxy, hydroxyl, amino, halo, nitro,alkylamino, acyl, cyano, carboxy, aminocarbonyl, alkoxycarbonyl andaralkoxycarbonyl. The term “heterocyclo” embraces saturated, partiallyunsaturated and unsaturated heteroatom-containing ring-shaped radicals,where the heteroatoms may be selected from nitrogen, sulfur and oxygen.Examples of saturated heterocyclo radicals include saturated 3 to6-membered heteromonocylic group containing 1 to 4 nitrogen atoms (e.g.pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atomsand 1 to 3 nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1to 3 nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of partiallyunsaturated heterocyclo radicals include dihydrothiophene, dihydropyran,dihydrofuran and dihydrothiazole. The term “heteroaryl” embracesunsaturated heterocyclo radicals. Examples of unsaturated heterocycloradicals, also termed “heteroaryl” radicals include unsaturated 3 to 6membered heteromonocyclic group containing 1 to 4 nitrogen atoms, forexample, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.) tetrazolyl (e.g.1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensedheterocyclo group containing 1 to 5 nitrogen atoms, for example,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g.,tetrazolo[1,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic groupcontaining a sulfur atom, for example, thienyl, etc.; unsaturated 3- to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl(e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.)etc.; unsaturated condensed heterocyclo group containing 1 to 2 oxygenatoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl,etc.); unsaturated 3 to 6-membered heteromonocyclic group containing 1to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclo groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g.,benzothiazolyl, benzothiadiazolyl, etc.) and the like. The term alsoembraces radicals where heterocyclo radicals are fused with arylradicals. Examples of such fused bicyclic radicals include benzofuran,benzothiophene, and the like. Said “heterocyclo group” may have 1 to 3substituents such as alkyl, hydroxyl, halo, alkoxy, oxo, amino andalkylamino. The term “alkylthio” embraces radicals containing a linearor branched alkyl radical, of one to about ten carbon atoms attached toa divalent sulfur atom. More preferred alkylthio radicals are “loweralkylthio” radicals having alkyl radicals of one to six carbon atoms.Examples of such lower alkylthio radicals are methylthio, ethylthio,propylthio, butylthio and hexylthio. The term “alkylthioalkyl” embracesradicals containing an alkylthio radical attached through the divalentsulfur atom to an alkyl radical of one to about ten carbon atoms. Morepreferred alkylthioalkyl radicals are “lower alkylthioalkyll” radicalshaving alkyl radicals of one to six carbon atoms. Examples of such loweralkylthioalkyl radicals include methylthiomethyl. The term“alkylsulfinyl” embraces radicals containing a linear or branched alkylradical, of one to ten carbon atoms, attached to a divalent—S(═O)—radical. More preferred alkylsulfinyl radicals are “loweralkylsulfinyl” radicals having alkyl radicals of one to six carbonatoms. Examples of such lower alkylsulfinyl radicals includemethylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl. The term“sulfonyl”, whether used alone or linked to other terms such asalkylsulfonyl, denotes respectively divalent radicals —SO₂—.“Alkylsulfonyl” embraces alkyl radicals attached to a sulfonyl radical,where alkyl is defined as above. More preferred alkylsulfonyl radicalsare “lower alkylsulfonyl” radicals having one to six carbon atoms.Examples of such lower alkylsulfonyl radicals include methylsulfonyl,ethylsulfonyl and propylsulfonyl. The “alkylsulfonyl” radicals may befurther substituted with one or more halo atoms, such as fluoro, chloroor bromo, to provide haloalkylsulfonyl radicals. The terms “sulfamyl”,“aminosulfonyl” and “sulfonamidyl” denote NH₂O₂S—. The term “acyl”denotes a radical provided by the residue after removal of hydroxyl froman organic acid. Examples of such acyl radicals include alkanoyl andaroyl radicals. Examples of such lower alkanoyl radicals include formyl,acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl,hexanoyl, trifluoroacetyl. The term “carbonyl”, whether used alone orwith other terms, such as “alkoxycarbonyl”, denotes —(C═O)—. The term“aroyl” embraces aryl radicals with a carbonyl radical as defined above.Examples of aroyl include benzoyl, naphthoyl, and the like and the arylin said aroyl may be additionally substituted. The terms “carboxy” or“carboxyl”, whether used alone or with other terms, such as“carboxyalkyl”, denotes —CO₂H. The term “carboxyalkyl” embraces alkylradicals substituted with a carboxy radical. More preferred are “lowercarboxyalkyl” which embrace lower alkyl radicals as defined above, andmay be additionally substituted on the alkyl radical with halo. Examplesof such lower carboxyalkyl radicals include carboxymethyl, carboxyethyland carboxypropyl. The term “alkoxycarbonyl” means a radical containingan alkoxy radical, as defined above, attached via an oxygen atom to acarbonyl radical. More preferred are “lower alkoxycarbonyl” radicalswith alkyl porions having 1 to 6 carbons. Examples of such loweralkoxycarbonyl (ester) radicals include substituted or unsubstitutedmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl andhexyloxycarbonyl. The terms “alkylcarbonyl”, “arylcarbonyl” and“aralkylcarbonyl” include radicals having alkyl, aryl and aralkylradicals, as defined above, attached to a carbonyl radical. Examples ofsuch radicals include substituted or unsubstituted methylcarbonyl,ethylcarbonyl, phenylcarbonyl and benzylcarbonyl. The term “aralkyl”embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl,triphenylmethyl, phenylethyl, and diphenylethyl. The aryl in saidaralkyl may be additionally substituted with halo, alkyl, alkoxy,halkoalkyl and haloalkoxy. The terms benzyl and phenylmethyl areinterchangeable. The term “heterocycloalkyl” embraces saturated andpartially unsaturated heterocyclo-substituted alkyl radicals, such aspyrrolidinylmethyl, and heteroaryl-substituted alkyl radicals, such aspyridylmethyl, quinolylmethyl, thienylmethyl, furylethyl, andquinolylethyl. The heteroaryl in said heteroaralkyl may be additionallysubstituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. Theterm “aralkoxy” embraces aralkyl radicals attached through an oxygenatom to other radicals. The term “aralkoxyalkyl” embraces aralkoxyradicals attached through an oxygen atom to an alkyl radical. The term“aralkylthio” embraces aralkyl radicals attached to a sulfur atom. Theterm “aralkylthioalkyl” embraces aralkylthio radicals attached through asulfur atom to an alkyl radical. The term “aminoalkyl” embraces alkylradicals substituted with one or more amino radicals. More preferred are“lower aminoalkyl” radicals. Examples of such radicals includeaminomethyl, aminoethyl, and the like. The term “alkylamino” denotesamino groups which have been substituted with one or two alkyl radicals.Preferred are “lower N-alkylamino” radicals having alkyl portions having1 to 6 carbon atoms. Suitable lower alkylamino may be mono ordialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino,N,N-diethylamino or the like. The term “arylamino” denotes amino groupswhich have been substituted with one or two aryl radicals, such asN-phenylamino. The “arylamino” radicals may be further substituted onthe aryl ring portion of the radical. The term “aralkylamino” embracesaralkyl radicals attached through an amino nitrogen atom to otherradicals. The terms “N-arylaminoalkyl” and “N-aryl-N-alkyl-aminoalkyl”denote amino groups which have been substituted with one aryl radical orone aryl and one alkyl radical, respectively, and having the amino groupattached to an alkyl radical. Examples of such radicals includeN-phenylaminomethyl and N-phenyl-N-methylaminomethyl. The term“aminocarbonyl” denotes an amide group of the formula —C(═O)NH₂. Theterm “alkylaminocarbonyl” denotes an aminocarbonyl group which has beensubstituted with one or two alkyl radicals on the amino nitrogen atom.Preferred are “N-alkylaminocarbonyl” “N,N-dialkylaminocarbonyl”radicals. More preferred are “lower N-alkylaminocarbonyl” “lowerN,N-dialkylaminocarbonyl” radicals with lower alkyl portions as definedabove. The term “alkylaminoalkyl” embraces radicals having one or morealkyl radicals attached to an aminoalkyl radical. The term“aryloxyalkyl” embraces radicals having an aryl radical attached to analkyl radical through a divalent oxygen atom. The term “arylthioalkyl”embraces radicals having an aryl radical attached to an alkyl radicalthrough a divalent sulfur atom.

The present invention comprises a pharmaceutical composition comprisinga therapeutically-effective amount of a leukotriene B₄ receptorantagonist and of a cyclooxygenase-2 inhibitor compound in associationwith at least one pharmaceutically-acceptable carrier, adjuvant ordiluent.

The present invention also comprises a method of treating inflammationor inflammation-associated disorders in a subject, the method comprisingadministering to the subject having or susceptible to such inflammationor disorder a therapeutically-effective amount of a leukotriene B₄receptor antagonist and of a cyclooxygenase-2 inhibitor. The method ofthe present invention also includes prophylactic or chronic treatment,especially in the case of arthritis and other inflammatory conditionswhich can lead to deterioration in the joints.

Also included in the family of compounds of Formula I are thepharmaceutically-acceptable salts thereof. The term“pharmaceutically-acceptable salts” embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. The nature of the salt is not critical, provided that it ispharmaceutically-acceptable. Suitable pharmaceutically-acceptable acidaddition salts of compounds of Formula I may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsare hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuricand phosphoric acid. Appropriate organic acids may be selected fromaliphatic, cycloaliphatic, aromatic; araliphatic, heterocycle,carboxylic and sulfonic classes of organic acids, example of which areformic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic,tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,aspartic, glutamic, benzoic, anthranilic, mesylic, p-hydroxybenzoic,phenylacetic, mandelic, embonic (pamoic), methanesulfonic,ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic,2-hydroxyethanesulfonic, sulfanilic, stearic, cyclohexylamincsulfonic,algenic, β-hydroxybutyric, salicylic, galactaric and galacturonic acid.Suitable pharmaceutically-acceptable base addition salts of compounds ofFormula I include metallic salts made from aluminum, calcium, lithium,magnesium, potassium, sodium and zinc or organic salts made fromN,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. All ofthese salts may be prepared by conventional means from the correspondingcompound of Formula I by reacting, for example, the appropriate acid orbase with the compound of Formula I.

GENERAL SYNTHETIC PROCEDURES

The cyclooxygenase-2 inhibitor compounds of the invention can besynthesized according to the following procedures of Schemes I-X,wherein the R¹-R³ substituents are as defined for Formula I, above,except where further noted.

Synthetic Scheme I shows the preparation of cyclooxygenase-2 inhibitorcompounds, as described in U.S. Pat. No. 5,466,823, which isincorporated by reference, embraced by Formula I where R is Ar or Z (asdefined in Scheme I), and R^(a) is a radical defined above for thesubstituents optionally substituted on A. In step 1, ketone 1 is treatedwith a base, preferably NaOMe or NaH, and an ester, or ester equivalent,to form the intermediate diketone 2 (in the enol form) which is usedwithout further purification. In step 2, diketone 2 in an anhydrousprotic solvent, such as absolute ethanol or acetic acid, is treated withthe hydrochloride salt or the free base of a substituted hydrazine atreflux to afford a mixture of pyrazoles 3 and 4. Recrystallization orchromatography affords 3 usually as a solid. Similar pyrazoles can beprepared by methods described in U.S. Pat. Nos. 4,146,721, 5,051,518,5,134,142 and 4,914,121 which also are incorporated by reference.

Scheme II shows the four step procedure for forming cyclooxygenase-2inhibitor pyrazoles 8 as described in U.S. Pat. No. 5,486,534 (whereR^(a) is alkyl) from ketones 5. In step 1, ketone 5 is reacted with abase, such as lithium bis(trimethylsilyl)amide or lithiumdiisopropylamide (LDA) to form the anion. In step 2, the anion isreacted with an acetylating reagent to provide diketone 6. In step 3,the reaction of diketone 6 with hydrazine or a substituted hydrazine,gives pyrazole 7. In step 4, the pyrazole 7 is oxidized with anoxidizing reagent, such as Oxone® (potassium peroxymonosulfate),3-chloroperbenzoic acid (MCPBA) or hydrogen peroxide, to give a mixtureof the desired 3-(alkylsulfonyl)phenyl-pyrazole 8 and the5-(alkylsulfonyl)phenyl-pyrazole isomer. The desired pyrazole 8, usuallya white or pale yellow solid, is obtained in pure form either bychromatography or recrystallization.

Alternatively, diketone 6 can be formed from ketone 5 by treatment witha base, such as sodium hydride, in a solvent, such as dimethylformamide,and further reacting with a nitrile to form an aminoketone. Treatment ofthe aminoketone with acid forms the diketone 6. Similar pyrazoles can beprepared by methods described in U.S. Pat. No. 3,984,431 which isincorporated by reference.

Cyclooxygenase-2 inhibitor diaryl/heteroaryl thiophenes (where T is S,and R^(b) is alkyl) can be prepared by the methods described in U.S.Pat. Nos. 4,427,693, 4,302,461, 4,381,311, 4,590,205, and 4,820,827, andPCT documents WO 95/00501 and WO 94/15932, which are incorporated byreference. Similar pyrroles (where T is N), furanones and furans (whereT is O) can be prepared by methods described in PCT documents WO95/00501 and WO 94/15932.

Cyclooxygenase-2 inhibitor diaryl/heteroaryl oxazoles can be prepared bythe methods described in U.S. Pat. Nos. 3,743,656, 3,644,499 and3,647,858, and PCT documents WO 95/00501 and WO 94/27980, which areincorporated by reference.

Cyclooxygenase-2 inhibitor diaryl/heteroaryl isoxazoles can be preparedby the methods described in U.S. application Serial No. 08/387,680, PCTdocuments WO92/05162, and WO92/19604, and European Publication EP 26928which are incorporated by reference. Sulfonamides 24 can be formed fromthe hydrated isoxazole 23 in a two step procedure. First, hydratedisoxazole 23 is treated at about 0° C. with two or three equivalents ofchlorosulfonic acid to form the corresponding sulfonyl chloride. In steptwo, the sulfonyl chloride thus formed is treated with concentratedammonia to provide the sulfonamide derivative 24.

Scheme VI shows the three step preparation of the cyclooxygenase-2inhibitor imidazoles 29 of the present invention. In step 1, thereaction of substituted nitrites (R¹CN) 25 with primary phenylamines 26in the presence of alkylaluminum reagents such as trimethylaluminum,triethylaluminum, dimethylaluminum chloride, diethylaluminum chloride inthe presence of inert solvents such as toluene, benzene, and xylene,gives amidines 27. In step 2, the reaction of amidine 27 with2-haloketones (where X is Br or Cl) in the presence of bases, such assodium bicarbonate, potassium carbonate, sodium carbonate, potassiumbicarbonate or hindered tertiary amines such asN,N′-diisopropylethylamine, gives the 4,5-dihydroimidazoles 28 (whereR^(b) is alkyl). Some of the suitable solvents for this reaction areisopropanol, acetone and dimethylformamide. The reaction may be carriedout at temperatures of about 20° C. to about 90° C. In step 3, the4,5-dihydroimidazoles 28 may be dehydrated in the presence of an acidcatalyst such as 4-toluenesulfonic acid or mineral acids to form the1,2-disubstituted imidazoles 29 of the invention. Suitable solvents forthis dehydration step are e.g., toluene, xylene and benzene.Trifluoroacetic acid can be used as solvent and catalyst for thisdehydration step.

In some cases (e.g., where YR=methyl or phenyl) the intermediate 28 maynot be readily isolable. The reaction, under the conditions describedabove, proceeds to give the targeted imidazoles directly.

Similarly, imidazoles can be prepared having the sulfonylphenyl moietyattached at position 2 and R¹ attached at the nitrogen atom atposition 1. Diaryl/heteroaryl imidazoles can be prepared by the methodsdescribed in U.S. Pat. Nos. 4,822,805, PCT document WO 96/03388 and PCTdocument WO 93/14082, which are incorporated by reference.

The subject imidazole cyclooxygenase-2 inhibitor compounds 36 of thisinvention may be synthesized according to the sequence outlined inScheme VII. Aldehyde 30 may be converted to the protected cyanohydrin 31by reaction with a trialkylsilyl cyanide, such as trimethylsilyl cyanide(TMSCN) in the presence of a catalyst such as zinc iodide (ZnI₂) orpotassium cyanide (KCN). Reaction of cyanohydrin 31 with a strong basefollowed by treatment with benzaldehyde 32 (where R² is alkyl) and usingboth acid and base treatments, in that order, on workup gives benzoin33. Examples of strong bases suitable for this reaction are lithiumdiisopropylamide (LDA) and lithium hexamethyldisilazane. Benzoin 33 maybe converted to benzil 34 by reaction with a suitable oxidizing agent,such as bismuth oxide or manganese dioxide, or by a Swern oxidationusing dimethyl sulfoxide (DMSO) and trifluoroacetic anhydride. Benzil 34may be obtained directly by reaction of the anion of cyanohydrin 31 witha substituted benzoic acid halide. Any of compounds 33 and 34 may beused as intermediates for conversion to imidazoles 35 (where R² isalkyl) according to chemical procedures known by those skilled in theart and described by M. R. Grimmett, “Advances in Imidazole Chemistry”in Advances in Heterocyclic Chemistry, 12, 104 (1970). The conversion of34 to imidazoles 35 is carried out by reaction with ammonium acetate andan appropriate aldehyde (RYCHO) in acetic acid. Benzoin 36 may beconverted to imidazoles 38 by reaction with formamide. In addition,benzoin 36 may be converted to imidazoles by first acylating with anappropriate acyl group (RYCO—) and then treating with ammoniumhydroxide. Those skilled in the art will recognize that the oxidation ofthe sulfide (where R² is methyl) to the sulfone may be carried out atany point along the way beginning with compounds 35, and includingoxidation of imidazoles 38, using, for examples, reagents such ashydrogen peroxide in acetic acid, m-chloroperoxybenzoic acid (MCPBA) andpotassium peroxymonosulfate (OXONE®).

Diaryl/heteroaryl imidazoles can be prepared by the methods described inU.S. Pat. Nos. 3,707,475, 4,686,231, 4,503,065, 4,472,422, 4,372,964,4,576,958, 3,901,908, PCT document WO 96/03387, European publication EP372,445, and PCT document WO 95/00501, which are incorporated byreference.

Diaryl/heteroaryl cyclopentene cyclooxygenase-2 inhibitors can beprepared by the methods described in U.S. Pat. No. 5,344,991, and PCTdocument WO 95/00501, which are incorporated by reference.

Similarly, Synthetic Scheme IX shows the procedure for the preparationof 1,2-diarylbenzene cyclooxygenase-2 inhibitor agents 44 from2-bromo-biphenyl intermediates 43 (prepared similar to that described inSynthetic Scheme VIII) and the appropriate substituted phenylboronicacids. Using a coupling procedure similar to the one developed by Suzukiet al. [Synth. Commun., 11, 513 (1981)], intermediates 43 are reactedwith the boronic acids in toluene/ethanol at reflux in the presence of aPd° catalyst, e.g., tetrakis(triphenylphosphine) palladium(0), and 2Msodium carbonate to give the corresponding 1,2-diarylbenzeneantiinflammatory agents 44 of this invention. Such terphenyl compoundscan be prepared by the methods described in U.S. application Ser. No.08/346,433 1333 U.S. Pat. No. 5,739,166, which is incorporated byreference.

Diaryl/heteroaryl thiazole cyclooxygenase-2 inhibitors can be preparedby the methods described in U.S. Pat. No. 4,051,250, 4,632,930, PCTdocument WO 96/03392, European Application EP 592,664, and PCT documentWO 95/00501, which are incorporated by reference. Isothiazoles can beprepared as described in PCT document WO 95/00501. Diaryl/heteroarylpyridine cyclooxygenase-2 inhibitors can be prepared by the methodsdescribed in U.S. Pat. Nos. 5,169,857, 4,011,328, 4,533,666, U.S.application Ser. No. 08/386,843, U.S Pat. No. 5,596,008 and U.S.application Ser. No. 08/387,150, U.S. Pat. No. 5,686,470 which areincorporated by reference. Diaryl/heteroaryl benzofuran derivatives canbe prepared by the methods described in U.S. application Ser. No.08/541,850 abandoned and U.S. application Ser. No. 08/540,522 abandonedwhich are incorporated by reference.

The following examples contain detailed descriptions of the methods ofpreparation of combinations with compounds of Formula I. These detaileddescriptions fall within the scope, and serve to exemplify, the abovedescribed General Synthetic Procedures which form part of the invention.These detailed descriptions are presented for illustrative purposes onlyand are not intended as a restriction on the scope of the invention. Allparts are by weight and temperatures are in Degrees centigrade unlessotherwise indicated. All compounds showed NMR spectra consistent withtheir assigned structures.

BIOLOGICAL EVALUATION

A combination therapy of a cyclooxygenase-2 inhibitor and a leukotrieneB₄ receptor antagonist could be evaluated as described in the followingtests.

EXAMPLE 14-[5-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

Step 1: Preparation of4,4,4-trifluoro-1-[4-(chloro)phenyl]-butane-1,3-dione.

Ethyl trifluoroacetate (23.52 g, 166 mmol) was dissolved in methyltert-butyl ether (75 mL). To the stirred solution was added 25 weight %sodium methoxide (40 mL, 177 mmol). Next 4′-chloroacetophenone (23.21 g,150 mmol) was dissolved in methyl tert-butyl ether (20 mL), and added tothe reaction dropwise. After stirring overnight (15.75 hours), 3N HCl(70 mL) was added. The organic layer was collected, washed with brine(75 mL), dried over MgSO₄, filtered, and concentrated in vacuo to give a35.09 g of yellow-orange solid. The solid was recrystallized fromisooctane to give 31.96 g (85%) of the dione: mp 66-67 ° C.

Step 2: Preparation of4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.

4-Sulphonamidophenyl hydrazine hydrochloride (982 mg, 4.4 mmol) wasadded to a stirred solution of4,4,4-trifluoro-1-[4-chlorophenyl]-butane-1,3-dione (1.00 g, 4.0 mmol)in ethanol (50 mL). The reaction was heated to reflux and stirred for 20hours. After cooling to room temperature, the reaction mixture wasconcentrated in vacuo. The residue was taken up in ethyl acetate andwashed with water and brine and dried over MgSO₄, filtered, andconcentrated in vacuo to give a light brown solid which wasrecrystallized from ethyl acetate and isooctane to give the pyrazole(1.28 g, 80%): mp 143-145 ° C. EI GC-MS M+=401.

EXAMPLE 24-[5-(3-Fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

Step 1: Preparation of 3′-fluoro-4′-methoxy-acetophenone.

Acetyl chloride (51.0 g, 0.65 mol) was added dropwise to a stirredsolution of aluminum chloride (80.0 g, 0.6 mol) and chloroform (750 mL),maintaining the temperature between 5-10° C. The mixture was stirred for10 minutes at 5 ° C. before the dropwise addition of 2-fluoroanisole(62.6 g, 0.5 mol). The mixture was stirred at 0-10° C. for 1 hour andpoured into ice (1 L). The resultant layers were separated and theaqueous layer was extracted with dichloromethane (2×250 mL). Thecombined organic layers were washed with water (2×150 mL), dried overanhydrous MgSO₄, filtered and concentrated in vacuo to a volume of 300mL. Hexanes were added and a white solid formed which was isolated byfiltration and air dried. This material was recrystallized from amixture of dichloromethane and hexanes to afford (77.2 g, 92%) ofmaterial suitable for use in the next step: mp 92-94° C.

Step 2: Preparation of4,4-difluoro-1-(3-fluoro-4-methoxyohenyl)-butane-1,3-dione.

Ethyl difluoroacetate (4.06 g, 32.7 mmol) was dissolved in methylt-butyl ether (50 mL). To the stirred solution was added 25 weight %sodium methoxide (7.07 g, 32.7 mmol) followed by3′-fluoro-4′-methoxyacetophenone (5.0 g, 29.7 mmol). After stirring for16 hours, 1N HCl (50 mL) was added. The organic layer was collected andwashed with water (2×50 mL), dried over anhydrous MgSO₄, filtered, andadded to hexanes to precipitate a tan solid (7.0 g, 96%): mp 70-72° C.

Step 3: Preparation of4-[5-(3-fluoro-4-methoxyhenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.

4,4-Difluoro-1-(3-fluoro-4-methoxyphenyl)-butane-1,3-dione from Step 2(7.0 g, 28.4 mmol) was dissolved in ethanol (150 mL). To the stirredmixture was added 4-sulphonamidophenyl hydrazine hydrochloride (7.4 g,33 mmol) and stirred at reflux overnight (16 hours). The mixture wascooled and water was added until crystals slowly appeared. The productwas isolated by filtration and air dried to provide the desired productas a light tan solid (9.8 g, 87%): mp 159-161 °C. Anal. Calc'd. forC₁₇H₁₄N₃SO₃F₃: C, 51.38; H, 3.55; N, 10.57. Found: C, 51.46; H, 3.52; N,10.63.

EXAMPLE 3

7-[3-[2-(Cyclopropylmethyl)-3-methoxy-4-[(methylamino)carbonyl]phenoxy]propoxy]-3,4-dihydro-8-propyl-2H1-benzopyran-2-propanoicacid is prepared as in U.S. Pat. No. 5,310,951, which is incorporated byreference.

Induction and Assessment of Collagen Induced Arthritis in Mice

Arthritis is induced in 8-12 week old male DBA/1 mice by injection of 50μg of chick type II collagen (CII) (provided by Dr. Marie Griffiths,Univ. of Utah, Salt Lake City, Utah) in complete Freunds adjuvant(Sigma) on day 0 at the base of the tail as previously described [J.Stuart, Annual Rev. Immunol., 2, 199 (1984)]. Compounds are prepared asa suspension in 0.5% methylcelluose (Sigma, St. Louis, Mo.), 0.025%Tween 20 (Sigma). The cyclooxygenase-2 inhibitors (Example 1 and 2) andleukotriene B₄ receptor antagonist (Example 3) are administered alone ora cyclooxygenase-2 inhibitor and a leukotriene B₄ receptor antagonist incombination. The compounds are administered in non-arthritic animals bygavage in a volume of 0.1 ml beginning on day 20 post collagen injectionand continuing daily until final evaluation on day 55. Animals areboosted on day 21 with 50 μg of collagen (CII) in incomplete Freundsadjuvant. The animals are subsequently evaluated several times each weekfor incidence and severity of arthritis until day 56. Any animal withpaw redness or swelling is counted as arthritic. Scoring of severity iscarried out using a score of 0-3 for each paw (maximal score of12/mouse) as previously described [P. Wooley, et al., Trians. Proc., 15,180 (1983)]. The animals are measured for incidence of arthritis andseverity in the animals where arthritis is observed. The incidence ofarthritis is determined at a gross level by observing the swelling orredness in the paw or digits. Severity is measured with the followingguidelines. Briefly, animals displaying four normal paws, i.e., noredness or swelling are scored 0. Any redness or swelling of digits orthe paw is scored as 1. Gross swelling of the whole paw or deformity isscored as 2. Ankylosis of joints is scored as 3.

Histological Examination of Paws

In order to verify the gross determination of a non-arthritic animal, ahistological examination is performed. Paws from animals sacrificed atthe end of the experiment are removed, fixed and decalcified aspreviously described [R. Jonsson, J. Immunol. Methods, 88, 109 (1986)].Samples are paraffin embedded, sectioned, and stained with hematoxylinand eosin by standard methods. Stained sections are examined forcellular infiltrates, synovial hyperplasia, and bone and cartilageerosion.

The animals are dosed at one of the following dosing ranges:

a - Example 1 @3 mpk/day; Example 3 @3 mpk/day;

b - Example 2 @30 mpk/day; Example 3 @10 mpk/day;

c - Example 2 @10 mpk/day; Example 3 @10 mpk/day;

d - Example 1 M,W,F @10 mpk/day; Example 3 @10 mpk/day.

EXAMPLE 4

A formulation is prepared having the following components:

700 mg of a cyclooxygenase-2 inhibitor and 700 mg of a leukotriene B₄receptor antagonist.

EXAMPLE 5

A formulation is prepared having the following components:

350 mg of4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamideand 350 mg of7-[3-[2-(cyclopropylmethyl)-3-methoxy-4-[(methylamino)carbonyl]phenoxy]propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propanoicacid.

Also embraced within this invention is a class of pharmaceuticalcompositions comprising the active compounds of this combination therapyin association with one or more non-toxic, pharmaceutically-acceptablecarriers and/or diluents and/or adjuvants (collectively referred toherein as “carrier” materials) and, if desired, other activeingredients. The active compounds of the present invention may beadministered by any suitable route, preferably in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. The active compounds andcomposition may, for example, be administered orally, intravascularly,intraperitoneally, subcutaneously, intramuscularly or topically.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. The active ingredient mayalso be administered by injection as a composition wherein, for example,saline, dextrose or water may be used as a suitable carrier.

The amount of therapeutically active compounds that are administered andthe dosage regimen for treating a disease condition with the compoundsand/or compositions of this invention depends on a variety of factors,including the age, weight, sex and medical condition of the subject, theseverity of the disease, the route and frequency of administration, andthe particular compound employed, and thus may vary widely. Thepharmaceutical compositions may contain active ingredients in the rangeof about 0.1 to 2000 mg, preferably in the range of about 0.5 to 500 mgand most preferably between about 1 and 100 mg. A daily dose of about0.01 to 100 mg/kg body weight, preferably between about 0.5 and about 20mg/kg body weight and most preferably between about 0.1 to 10 mg/kg bodyweight, may be appropriate. The daily dose can be administered in one tofour doses per day.

In the case of psoriasis and other skin conditions, it may be preferableto apply a topical preparation of compounds of this invention to theaffected area two to four times a day.

For inflammations of the eye or other external tissues, e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream, or as a suppository, containing the active ingredients in a totalamount of, for example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w andmost preferably 0.4 to 15% w/w. When formulated in an ointment, theactive ingredients may be employed with either paraffinic or awater-miscible ointment base. Alternatively, the active ingredients maybe formulated in a cream with an oil-in-water cream base. If desired,the aqueous phase of the cream base may include, for example at least30% w/w of a polyhydric alcohol such as propylene glycol,butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol andmixtures thereof. The topical formulation may desirably include acompound which enhances absorption or penetration of the activeingredient through the skin or other affected areas. Examples of suchdermal penetration enhancers include dimethylsulfoxide and relatedanalogs. The compounds of this invention can also be administered by atransdermal device. Preferably topical administration will beaccomplished using a patch either of the reservoir and porous membranetype or of a solid matrix variety. In either case, the active agent isdelivered continuously from the reservoir or microcapsules through amembrane into the active agent permeable adhesive, which is in contactwith the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent is administered to the recipient. In the case ofmicrocapsules, the encapsulating agent may also function as themembrane.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier, it may comprise a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,among others.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties, since the solubility of theactive compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredients are dissolved or suspended insuitable carrier, especially an aqueous solvent for the activeingredients. The antiinflammatory active ingredients are preferablypresent in such formulations in a concentration of 0.5 to 20%,advantageously 0.5 to 10% and particularly about 1.5% w/w.

For therapeutic purposes, the active compounds of this combinationinvention are ordinarily combined with one or more adjuvants appropriateto the indicated route of administration. If administered per os, thecompounds may be admixed with lactose, sucrose, starch powder, celluloseesters of alkanoic acids, cellulose alkyl esters, talc, stearic acid,magnesium stearate, magnesium oxide, sodium and calcium salts ofphosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules having one or more of the carriers or diluents mentioned foruse in the formulations for oral administration. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, and/or various buffers. Other adjuvants and modes ofadministration are well and widely known in the pharmaceutical art.

Although this invention has been described with respect to specificembodiments, the details of these embodiments are not to be construed aslimitations.

What is claimed is:
 1. A method of treating inflammation or aninflammation-associatcd disorder in a subject, said method comprisingco-administering to the subject having or susceptible to suchinflammation or inflammation-associated disorder, atherapeutically-effective amount of a leukotriene B₄ receptor antagonistand a cyclooxygenase-2 inhibitor selected from Taisho NS-398(Methanesulfanimide, N-[2-(cyclohexyloxy)-4-nitrophenyl]), meloxicam(2H-1,2-Benzothiazine-3-carboxamide,4-hydroxy-2-methtyl-N-(5-metlhyl-2-thiazolyl)-, 1,1-dioxide), flosulide(Methanesulfonamide,N-[6-(2,4-difluorophenoxy)-2,3-dihydro-1-oxo-1H-inden-5-yl]), MerckMK-966 (2(5H)-Furanone, 4-[4-(methylsulfonyl)phenyl]-3-phenyl) andcompounds of Formula I

wherein A is a substituent selected from partially unsaturated orunsaturated heterocyclyl and partially unsaturated or unsaturatedcarbocyclic rings; wherein R¹ is at least one substituent selected fromheterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R¹ isoptionally substituted at a substitutable position with one or moreradicals selected from alkyl, haloalkyl, cyano, carboxyl,alkoxycarbonyl, hydroxyl, hydroxyalkyl, halcalkoxy, amino, alkylamino,arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy, andalkylthio; wherein R² is methyl or amino; and wherein R³ is a radicalselected from hydrido, halo, alkyl, alkenyl, alkynyl, oxo, cyano,carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio,alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalkcenyl,aralkyl, heterocyclylalkyl, acyl, alkythioalkyl, hydroxyalkyl,alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl,arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl,alkoxyalralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl,aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl,N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl,alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino,N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl,N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl,N-alkyl-N-araylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio,alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl,N-arylaminosulfonyl, arylsulfonyl, N-alkyl-N-arylaminosulfonyl; or apharmaceutially-acceptable salt thereof.
 2. The method of claim 1wherein said leukotriene B₄ receptor antagonist and said cycloxygenase-2inhibitor are administered in a sequential manner.
 3. The method ofclaim 1 wherein said leukotriene B₄ receptor antagonist and saidcycloxygenase-2 inhibitor are administered in a substantiallysimultaneous manner.
 4. The method of claim 1 wherein the leukotriene B₄receptor antagonist is selected from Bayer Bay-x-1.005((R)-a-Cyclopentyl-4-(2-quinolinylmethoxy)benzeneacetic acid),Ciba-Geigy CGS-25019C (Benzamide,4-[[5-[4-(aminoiminomethyl)phenoxy]pentyl]oxy]-3-methoxy-N,N-bis(1-methylethyl)-,(2Z)-2-butenedioate), ebselen (1,2-Benzisoselenazol-3(2H)-one,2-phenyl), Leo Denmark ETI-615 (Benzoic acid,4-[[[(3-fluorophenyl)methyl][4-(2-quinolinylmethoxy)phenyl]amino]methyl]),Lilly LY-293111 (Benzoic acid,2-[3-[3-[(5-ethyl-4′-fluoro-2-hydroxy[1,1′-biphenyl]-4-yl)oxy]propoxy]-2-propylphenoxy]),Ono ONO-4057 (Benzenepropanoic acid,2-(4-carboxybutoxy)-6-[[(5E)-6-(4-methoxyphenyl)-5-hexenyl]oxy]), TerumoTMK-688 (Carbonic acid, 4-[5-[[2-[4-(diphenylmethoxy)-1-piperidinyl]ethyl]amino]-5-oxo-1,3-pentadienyl]-2-methoxyphenylethyl ester), Boehringer Ingleheim BI-RM-270 (2-Benzoxazolamine,N-[(1S)-2-cyclolhexyl-1-(2-pyridinyl)ethyl]-5-methyl), Lilly LY 213024(Benzenepropanoic acid, 5-(3-carboxybenzoyl)-2-(decyloxy) ), Lilly LY264086 (9H-Xanthene-4-propanoic acid, 7-carboxy-3-(decyloxy)-9-oxo) OnoONO LB457 (Benzenepropanoic acid,2-(4-carboxybutoxy)-6-[[(5E)-6-(4-methoxyphenyl)-5-hexenyl]oxy]), PerdueFrederick PF 10042 (Pyrrolidine,1-[5-hydroxy-5-[8-(1-hydroxy-2-phenylethyl)-2-dibenzofuranyl]-1-oxopentyl]),Rhone-Poulenc Rorer RP 66153 (2-Thiopheneheptanoic acid, .alpha.,.alpha.-dimethyl-3-(3-phenylpropyl)), SmithKline Beecham SB-201146(2-Propenoic acid, 3-[6-[[(3-aminnophenyl)sulfinyl]methyl]-3-[[(8-(4-methoxyphenyl)octyl]oxy]-2-pyridinyl]-, (2E)), SmithKline BeechamSB-201993 (Benzoic acid, 3-[[[[6[(1E)-2-carboxyethenyl]-5-[[8-(4-methoxyphenyl)octyl]oxy]-2-pyridinyl]methyl]thio]methyl]),Searle SC-53228 (2H-1-Benzopyran-2-propanoic acid,7-[3-[2-(cyclopropylmethyl)-3-methoxy-4-[(methylamino)carbonyl]phenoxy]propoxy]-3,4-dihydro-8-propyl-,(2S)),Sumitamo SM 15178 (.beta.-Alanine,N-[[6-[(4-acetyl-2-ethyl-5-hydroxyphenoxy) methyl]-2-pyridinyl]carbonyl]-N-ethyl), and 2, American Home Products WAY 121006([1,1′-Biphenyl]-4-acetic acid, 2-fluoro-4′-(2-quinolinylmethoxy)). 5.The method of claim 4 wherein the leukotriene B₄ receptor antagonist isselected from Bayer Bay-x-1005((R)-a-Cyclopentyl-4-(2-quinolinylmethoxy)benzeneacetic acid),Ciba-Geigy CGS-25019C (Benzamide,4-[[5-[4-(aminoiminomethyl)phenoxy]pentyl]oxy]-3-methoxy-N,N-bis(1-methylethyl)-,(2Z)-2-butenedioatc), ebselen (1,2-Benzisoselenazol-3(2H)-one,2-phenyl), Leo Denmark ETH-615 (Benzoic acid,4-[[[(3-fluorophenyl)methyl][4-(2-quinolinylmethoxy)phenyl]amino]methyl]),Lilly LY-293111 (Benzoic acid,2-[3-[3-[(5-ethyl-4′-fluoro-2-hydroxy[1,1′-biphenyl]-4-yl)oxy]propoxy]-2-propylphenoxy]),Ono ONO-4057 (Benzenepropanoic acid,2-(4-carboxybutoxy)-6[[(5E)-6-(4-methoxyphenyl)-5-hexenyl]oxy]), andTerumo TMK-688 (Carbonic acid,4-[5-[[2-[4-(diphenylmethoxy)-1-piperidinyl]ethyl]amino]-5-oxo-1,3-pentadienyl]2-methoxyphenylethel ester).
 6. The method of claim 1 wherein A is selected from 5- or6-member partially unsaturated heterocyclyl, 5- or 6-member unsaturatedheterocyclyl, 9- or 10-member unsaturated condensed heterocyclyl, lowercycloalkenyl and phenyl; wherein R¹ is selected from 5- and 6-memberedheterocyclyl, lower cycloalkyl, lower cycloalkenyl and aryl selectedfrom phenyl, biphenyl and naphthyl, wherein R¹ is optionally substitutedat a substitutable position with one or more radicals selected fromlower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl,hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino,phenylamino, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxyand lower alkylthio; wherein R² is methyl or amino; and wherein R³ is aradical selected from hydrido, oxo, cyano, carboxyl, loweralkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, halo, lower alkyl,lower alkyloxy, lower cycloalkyl, phenyl, lower haloalkyl, 5- or6-membered heterocyclyl, lower hydroxylalkyl, lower aralkyl, acyl,phenylcarbonyl, lower alkoxyalkyl, 5- or 6-membered heteroaryloxy,aminocarbonyl, lower alkylaminocarbonyl, lower alkylamino, loweraminoalkyl, lower alkylaminoalkyl, phenyloxy, and lower aralkoxy; or apharmaceutically-acceptable salt thereof.
 7. The method of claim 6wherein A is selected from oxazolyl, isoxazolyl, thienyl, dihydrofuryl,furyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, isothiazolyl,benzofuryl, cyclopentenyl, cyclopentadienyl, phenyl, and pyridyl;wherein R¹ is selected from pyridyl optionally substituted at asubstitutable position with one or more methyl radicals, and phenyloptionally substituted at a substitutable position with one or moreradicals selected from methyl, ethyl, isopropyl, butyl, tert-butyl,isobutyl, pentyl, hexyl, cyano, fluoromethyl, difluoromethyl,trifluoromethyl, carboxyl, methoxycarbonyl, ethoxycarbonyl,hydroxymethyl, trifluoromethoxy, hydroxyl, amino, N-methylamino,N,N-dimethylamino, N-ethylamino, N,N-dipropylamino, N-butylamino,N-methyl-N-ethylamino, phenylamino, methoxymethyl, methylsulfinyl,fluoro, chloro, bromo, methoxy, ethoxy, propoxy, n-butoxy, pentoxy, andmethylthio; wherein R² is methyl or amino; and wherein R³ is a radicalselected from hydrido, oxo, cyano, carboxyl, methoxycarbonyl,ethoxycarbonyl, carboxypropyl, carboxymethyl, carboxyethyl, cyanomethyl,fluoro, chloro, bromo, methyl, ethyl, isopropyl, butyl, tert-butyl,isobutyl, pentyl, hexyl, difluoromethyl, trifluoromethyl,pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl,methoxy, ethoxy, propoxy, n-butoxy, pentoxy, cyclohexyl, phenyl,pyridyl, thienyl, thiazolyl, oxazolyl, furyl, pyrazinyl, hydroxylmethyl,hydroxylpropyl, benzyl, formyl, phenylcarbonyl, methoxymethyl,furylmethyloxy, aminocarbonyl, N-methylaminocarbonyl,N,N-dimethylaminocarbonyl, N,N-dimethylamino, N-ethylamino,N,N-dipropylamino, N-butylamino, N-methyl-N-ethylamino, aminomethyl,N,N-dimethylaminomethyl, N-methyl-N-ethylaminomethyl, benzyloxy, andphenyloxy; or a pharmaceutically-acceptable salt thereof.
 8. The methodof claim 7 selected from compounds and their pharmaceutically-acceptablesalts, of the group consisting of4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;2-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide;4-[5-hydroxyethyl-3-phenylisoxazol-4-yl]benzenesulfonamide;[2-trifluoromethyl-5-(3,4-difluorophenyl)-4-oxazolyl]benzenesulfonamide;4-[2-methyl-4-phenyl-5-oxazoly]benzenesulfonamide; and4-[5-(3-fluoro-4-methoxyphenyl-2-trifluoromethyl)-4-oxazolyl]benzenesulfonamide.9. The method of claim 1 wherein the condition is inflammation.
 10. Themethod of claim 1 wherein the condition is an inflammation-associateddisorder.
 11. The method of claim 10 wherein the inflammation-associateddisorder is arthritis.
 12. The method of claim 1 wherein the subject issusceptible to inflammation.
 13. The method of claim 1 wherein thesubject is susceptible to an inflammation-associated disorder.
 14. Themethod of claim 13 wherein the subject is susceptible to arthritis.